Angela J. Hanson

Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer's Disease Dementia

Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimers disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.

Effect of apolipoprotein e genotype and diet on apolipoprotein e lipidation and amyloid peptides randomized clinical trial

IMPORTANCE Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the β-amyloid (Aβ) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aβ, and LD Aβ peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid. OBJECTIVE To characterize the lipidation states of Aβ peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention. DESIGN Randomized clinical trial. SETTING Veterans Affairs Medical Center clinical research unit. PARTICIPANTS Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years). INTERVENTIONS Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein). MAIN OUTCOMES AND MEASURES Lipid-depleted Aβ42 and Aβ40 and apolipoprotein E in cerebrospinal fluid. RESULTS Baseline levels of LD Aβ were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aβ42, P = .05; LD Aβ40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD Aβ levels, whereas the High diet increased these fractions (LD Aβ42, P = .01; LD Aβ40, P = .15). Changes in LD Aβ levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aβ42 and insulin, r = -0.68 [P = .01]; LD Aβ40 and insulin, r = -0.78 [P = .002]). CONCLUSIONS AND RELEVANCE The lipidation states of apolipoproteins and Aβ peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer’s Disease Biomarkers: A Pilot Clinical Trial

Background: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer’s disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers. Objective: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD. Methods: This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer’s Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers. Results: The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio. Conclusion: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

The APOE Genotype: Modification of Therapeutic Responses in Alzheimer's Disease

The translation of promising preclinical treatments into effective drugs for Alzheimers disease (AD) has been challenging. One of the most potent risk factors for sporadic AD is carrier status of the epsilon 4 allele of the apolipoprotein E gene (E4). E4 carriers show a differential response to several therapies which are being investigated as AD treatments, including acetylcholinesterase inhibitors and therapeutics with vascular and metabolic targets. The differential treatment responses of E4 carriers may partially explain why some treatments show a null effect in clinical trials. Understanding the reasons behind these responses is not only important for clinical practice, but may also help us elucidate mechanisms for this neurodegenerative disease.

Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment.

BACKGROUND High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimers disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions. OBJECTIVE To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor. METHODS 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimers disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations. RESULTS E4-adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p = 0.03). These findings were associated with meal-induced changes in glucose (p = 0.05), insulin (p = 0.004), triglycerides (p <  0.01), and plasma Aβ42 (p = 0.05). CONCLUSIONS These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.

Blood-Brain Barriers in Obesity

After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer’s disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis. In this article, we address how obesity affects the structure and function of the blood-brain barrier (BBB), the impact of obesity on Alzheimer’s disease, the effects of obesity on circulating proteins and their transport into the brain, and how these changes can potentially be reversed by weight loss.

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

An increased risk for Alzheimers disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimers disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimers disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimers disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimers disease.

Apolipoprotein E Genotype and Sex Influence Glucose Tolerance in Older Adults: A Cross-Sectional Study

Background: Glucose intolerance and apolipoprotein ε4 allele (E4+) are risk factors for Alzheimers disease (AD). Insulin sensitizers show promise for treating AD, but are less effective in E4+ individuals. Little is known about how the APOE genotype influences glucose metabolism. Methods: Cross-sectional analysis of 319 older adults who underwent oral glucose tolerance tests; a subset had insulin, amyloid beta (Aβ42), and Mini Mental Status Examination. Glucose and insulin patterns with respect to cognitive diagnosis, E4 status, and sex were examined with analysis of covariance and Pearson correlation. Results: People with cognitive impairment had higher fasting insulin levels. E4 status did not affect fasting glucose values, whereas men had higher fasting glucose levels than women. E4+ men had the lowest and E4+ women had the highest glucose levels, compared to E4- groups; insulin did not differ by sex or E4 group. E4 status and sex moderated correlations between metabolic measures and AD risk factors including age and Aβ. Conclusions: Insulin resistance was associated with cognitive impairment, and sex, E4 status, and glucose values are interrelated in older adults at risk of AD. Understanding glucose metabolism for different APOE and sex groups may help elucidate differences in therapeutic responses.

THE EFFECTS OF DIET INTERVENTION ON METABOLIC HEALTH AND CEREBRAL SPINAL FLUID ALZHEIMER’S DISEASE BIOMARKERS: A RANDOMIZED TRIAL

baseline RAQ scores predicted trial completion and study medication compliance. Youden index was used to estimate optimal cut points. Results: Mean baseline patient RAQ was 31.4 (95%CI 27.0 to 34.7) and mean study partner RAQ was 29.6 (95%CI 24.7 to 33.4). Both patient and study partner RAQ scores at baseline appeared similar to the respective scores at weeks 26 and 52 (all p>0.05). Higher baseline patient RAQ score predicted higher probability of compliance with study medication at weeks 26 and 52 (both p<0.05). Higher baseline study partner RAQ predicted higher probability of trial completion (OR 1⁄4 1.13; p<0.05). Larger disparity between patient and partner RAQ scores predicted lower probability of trial completion (OR1⁄4 0.95; p<0.05). A cut point of 28 optimally discerned between patients who did and did not complete the trial or would be unlikely to be compliant with study medications at a given study visit. In contrast, slightly lower cut points discerned between study partners, 27 and 24 for completion and compliance, respectively. Conclusions:The RAQ may help identify patients and study partners at risk of dropout. Further study is needed in diverse groups and to develop interventions to address the needs of participants identified as at risk for trial dropout.

APOE GENOTYPE INFLUENCES BRAIN TO BLOOD GLUCOSE RATIOS AFTER HIGH FAT FEEDING

25-hydroxyvitamin D by electrochemiluminescence in samples from a subset of participants from each trial arm (n1⁄4 780). The cutoffs for each were based on existing literature. NRI scores ranged from 0 (all 3 optimum) to 3 (all 3 suboptimum). The cognitive composite Z scores collected over 3 years in the parent MAPTwere fit with linear mixed-effects models. Results:Mean age was 75 (4.5), 67% were women, mean MMSE was 28 (1.6) and 20.7% carried an APOE4 allele. Over half of the population presented with nutritional risk (57.1% with NRI 1⁄4 1) and 31.6% with NRI 1⁄4 2. In adjusted mixed models, each unit increase in the NRI was associated with an annual incremental increase in rates of cognitive decline compared to those without nutritional risk (NRI 1⁄4 0) (e.g., NRI 1⁄4 1 (b 1⁄4 -0.04, p 1⁄4 0.0325); NRI 1⁄4 2 (b 1⁄4 -0.08, p < 0.0001); NRI 1⁄4 3 (b 1⁄4 -0.10, p 1⁄4 0.0017). Subjects with NRI 1⁄4 0 appreciated a 0.03 annual unit increase in their cognitive composite Z score over 3 years. Further controlling for APOE4, trial arm, baseline cognitive state and their interactions with time did not materially change the results. Conclusions: This biomarker-based Nutritional Risk Index that includes omega 3 fatty acids, vitamin D and homocysteine explains the heterogeneity observed in rates of cognitive decline in older non-demented adults with subjective memory concerns. Whether reducing nutritional risk by optimizing these nutritional biomarkers can slow cognitive decline will require formal clinical trial testing. The prudent deployment of nutritional biomarkers will advance clinical trials and deepen our understanding of nutrition and brain health.